Liquid Dosage Forms
Liquid dosage forms of insoluble compounds can provide a useful means of administration for subjects who have difficulty swallowing. In particular in the field of pharmaceuticals ease of administration may also help ensure optimal patient compliance. Additionally liquid form allows for a continuously variable dose quantity to be administered.
Many liquid doses forms of insoluble compounds are known from the art. For example, Altacite Plus Suspension (Peckforton Pharmaceuticals Limited) is sold as an antacid for the symptomatic relief of dyspepsia, flatulence and abdominal hyperacidity, gastritis, peptic ulceration, heartburn especially when associated with hiatus hernia, or heartburn during pregnancy. One of the active ingredients is ‘hydrotalcite light’, aluminium magnesium carbonate hydroxide hydrate. Altacite displays a yield stress of only 1 Pa and at this low yield stress would not be suitable for maintaining stable formulations wherein the active ingredient is of a hydrotalcite type comprising magnesium and iron or it is of insufficient yield stress to provide a stable formulation at a desirable particle size. and or dose level
Another product from Peckforton Pharmaceuticals Limited, Hydrotalcite Suspension, also contains hydrotalcite. The formulation also contains Veegum regular which is a magnesium aluminum silicate used to alter the rheology of liquid formulation. However, as this is an aluminium source this product is not considered suitable for kidney patients.
Talcid is intended for the symptomatic relief in cases of heartburn, stomach hyperacidity. The active ingredient is ‘hydrotalcite light’, aluminium magnesium carbonate hydroxide hydrate, which suffers from the same drawback of aluminium release and accumulation. Furthermore, the formulation contains bentonite which at higher concentrations can modify the rheological characteristics of the formulation. Bentonite is a calcium hydrated aluminosilicate which may also release aluminium. Carboxymethylcellulose sodium is used as a thickening agent. Talcid displays some yield stress but insufficient to provide a stable formulation at a desirable particle size.
The delivery of mixed metal compound is particularly problematic because mixed metal compounds typically have a high particulate density (such as a density of around 1.9 g/ml). Due to the large difference in density between such compounds and that of typical aqueous carrier fluids, mixed metal compounds have a propensity to settle out on storage. The rheology of the carrier fluid may be modified to increase the viscosity of the fluid and hence slow the settling rate of the suspended solids. However because of the atypical high particulate density this has the disadvantage that whilst the settling rate is reduced settling will still occur over a relatively short time frame. Furthermore, the high fluid viscosity makes it difficult to re-disperse any settled mixed metal compound.
U.S. Pat. No. 4,689,219 describes compositions comprising mixtures of xanthan gum and locust bean gum in a specified range of ratios. The formulation is packaged as a dry granule mix which is added to a drink immediately prior to consumption.
WO2007/135362 describes a formulation based on xanthan gum, PVP and glycerol containing a suspended non-steroidal anti-inflammatory drug where PVP acts a dispersant and glycerol as a density increasing agent. The optimal PVP concentration disclosed is 0.5 to about 3.5% w/v. Further, the suspended non-steroidal anti-inflammatory drug is present at a concentration of up to 5% w/v. This compares to required delivery levels of typically 10% w/v for mixed metal compounds.
IE153343 discloses an aqueous suspension concentrate composition of pendimethalin, a pesticide. More specifically, IE153343 discloses the use of a suspending agent, such as xanthan gum, at a concentration between 0.02 and 3.0% w/v, in combination with thickening agents such as polyvinyl-pyrrolidone (PVP). The proposed compositions also include surfactants, dispensing agents or wetting agents and an antifoaming agent to provide a stable suspension.
U.S. Pat. No. 5,300,302 discloses a pharmaceutical delivery system comprising a composition comprising an drug homogeneously distributed in a water-dispersible gel excipient containing either xanthan gum or a mixture of xanthan gum and methyl cellulose.
WO 03/013473 A1 teaches a colloidal silicon dioxide which may be combined with xanthan gum and a wetting agent in order to produce a suspension of drug particles that is substantially stable. It is stated that silicon dioxide has a synergistic effect with xanthan gum and produces a more stable suspension than otherwise possible
U.S. Pat. No. 5,112,604 discloses an aqueous formulation containing a drug substance; colloidal silicon dioxide; a hydrocolloid gum; a wetting agent; an antifoaming agent and a carbohydrate, which is stable for 90 days.
U.S. Pat. No. 7,300,670 discloses an aqueous pharmaceutical suspension for oral administration comprising at least one particulate drug with a density of from about 0.9 to about 1.6 g/ml and an average particle size less than about 20 micron; at least one suspending polymer exhibiting plastic flow with or without additional viscosity-building agents that provides a yield value to the final suspension of about 0.2 to about 15 Pa and an apparent viscosity at 100 sec−1 of at least about 50 cps; a liquid phase with an absolute density difference from each particulate drug of less than about 0.2 g/ml.
To provide sterile compositions, the prior art has taught that liquid compositions may be irradiated. For example, U.S. Pat. No. 5,273,767 discloses a modified, rapidly hydrating xanthan gum, prepared by irradiating non-irradiated xanthan gum with ionizing radiation, and furthermore a process for sterilizing a food product comprising non-irradiated xanthan gum as a gelling hydrocolloid.
Although irradiation may provide sterility, it presents a number of problems when applied to liquids containing insoluble products. For example, “Formulation of a Sterile Surgical Lubricant”, Adams, I., S. S. Davis and R, Kenshaw. 1972, J. Pharm. Pharmacol., 24:178P describes the complete loss of gel structure in methyl celluloses following irradiation. Applied Radiation Chemistry By Robert James Woods and Alekse{hacek over (i)} Konstantinovich Pikaev teaches us that a standard irradiation doses of 25 kGy is used in many countries, and 35 kGy in Scandinavian countries, but that by control of the production environment microbial contamination can be reduced to levels down to 10 kGy. (Publisher Wiley-IEEE, 1994, ISBN 0471544523, 9780471544524). U.S. Pat. No. 7,259,192 describes the depolymerization by high energy electron beam irradiation of xanthan gum at a preferred dose of 10 to 150 kGy.